Pancreatic Cancer Gastrointestinal Tract

Similar฀results฀have฀been฀obtained฀in฀further฀studies฀ [340–344] .฀Smoking฀cessation฀could฀ eliminate฀25฀of฀deaths฀from฀pancreatic฀cancer฀in฀the฀United฀States฀ [343] .฀Current฀cigar฀ smoking,฀especially฀when฀the฀smoke฀is฀inhaled,฀is฀also฀associated฀with฀an฀increased฀risk฀ for฀pancreatic฀cancer฀RR฀=฀2.7;฀CI:฀1.5–4.8฀ [345] .

7.6 Urinary Tract Diseases

Along฀with฀the฀lungs฀and฀heart,฀kidneys฀are฀among฀the฀most฀important฀target฀organs฀for฀the฀ harmful฀effects฀of฀smoking.฀In฀terms฀of฀preserving฀renal฀function฀in฀an฀older฀population,฀ smoking฀is฀counterproductive฀because฀pre-existing฀hypertension฀and฀vascular฀disease,฀in฀ tandem฀with฀smoking,฀will฀damage฀small฀and฀large฀renal฀vessels,฀even฀in฀patients฀without฀ diabetes฀ [346] .฀As฀long฀ago฀as฀1907,฀the฀German฀physician฀Hesse฀advised฀his฀patients฀with฀ nephrosclerosis฀to฀give฀up฀smoking฀ [347] . Sections฀of฀myocardium฀and฀kidney฀from฀autopsied฀subjects฀display฀parallel฀smoking- related฀changes฀in฀terms฀of฀increased฀intima฀thickness฀of฀small฀vessels;฀while฀the฀degree฀of฀ increase฀did฀not฀correlate฀with฀pack-years,฀it฀did฀show฀a฀positive฀correlation฀with฀age฀in฀the฀ kidney฀ [348] .฀ Within-subject฀ variability฀ has฀ so฀ far฀ limited฀ the฀ usefulness฀ of฀ biomarker฀ determinations฀ –฀ e.g.฀ microalbumin,฀ N-acetyl-b- d -glucosaminidase฀ NAG฀ and฀ alanine฀ aminopeptidase฀AAP฀–฀for฀the฀diagnosis฀of฀renal฀function฀ [349] .฀Whereas฀acute฀smoking฀ has฀been฀reported฀to฀have฀no฀inluence฀on฀renal฀albumin฀excretion฀ [350] ,฀microalbuminu- ria฀is฀already฀increased฀in฀the฀presence฀of฀diabetic฀changes฀see฀Sect.฀7.4.2.2. Smoking-induced฀elevations฀in฀blood฀pressure฀and฀heart฀rate฀result฀from฀increased฀secre- tion฀of฀arginine฀vasopressin฀and฀adrenaline,฀whereas฀glomerular฀iltration฀rate฀GFR฀falls฀with฀ a฀simultaneous฀increase฀in฀renal฀vascular฀resistance฀Fig.฀ 7.5 ฀ [351] .฀Overall,฀non-smokers฀ MAP HR GFR ERPF RVR −20 −10 10 20 Nicotine-induced changes [] 30 Nonsmoker smoker 40 Fig. 7.5 ฀฀฀Mean฀percentage฀ changes฀in฀mean฀arterial฀ pressure฀MAP,฀heart฀rate฀ HR,฀glomerular฀iltration฀ rate฀GFR,฀effective฀renal฀ plasma฀low฀ERPF฀and฀ renal฀vascular฀resistance฀ RVR฀in฀9฀smokers฀and฀฀ 10฀non-smokers฀following฀ administration฀of฀4-mg฀ nicotine฀chewing฀gum฀for฀฀ 30฀min฀ [351] respond฀more฀intensively฀than฀smokers฀to฀the฀administration฀of฀nicotine,฀suggesting฀that฀years฀ of฀smoking฀produce฀a฀diminished฀response฀or฀tachyphylaxis฀ [351,฀352] . Stress-related฀urinary฀incontinence฀develops฀primarily฀in฀smokers฀despite฀their฀higher฀ urethral฀sphincter฀tone;฀it฀is฀concluded฀that฀the฀simultaneous฀and฀persistent฀presence฀of฀vio- lent฀coughing฀in฀smokers฀overcomes฀the฀advantage฀of฀a฀stronger฀urethral฀sphincter฀ [353] . The฀development฀of฀renal฀and฀lower฀urinary฀tract฀tumours฀is฀associated฀with฀genetic฀ defects฀in฀detoxifying฀enzymes฀e.g.฀the฀cytochrome฀P450฀system,฀and฀the฀aromatic฀amine฀ acetyltransferases฀NAT-1฀and฀NAT-2฀ [354] ฀and฀with฀the฀accumulation฀of฀heavy฀metals,฀ such฀as฀cadmium.฀In฀men฀particularly,฀but฀also฀in฀women,฀the฀incidence฀of฀cancers฀of฀the฀ kidneys,฀bladder฀and฀genitalia฀increases฀as฀a฀function฀of฀pack-years฀of฀smoking,฀as฀shown฀ by฀one฀study฀from฀Finland฀ [355] ฀and฀a฀26-year฀follow-up฀study฀from฀Sweden฀ [356] .

7.6.1 Toxic Substances and Inducers

Cadmium:฀Differences฀in฀total฀body฀cadmium฀burden฀were฀identiied฀years฀ago฀between฀ non-smokers฀19.3฀mg฀and฀smokers฀35.5฀mg;฀average฀38.7฀pack-year฀smoking฀history฀ at฀age฀50,฀and฀cadmium฀is฀also฀known฀to฀be฀nephrotoxic฀ [357] .฀The฀renal฀cadmium฀burden฀ increases฀ with฀ age฀ [358] ,฀ only฀ to฀ decline฀ again฀ after฀ the฀ age฀ of฀ 60.฀ Cigarette฀ smoking฀ results฀in฀the฀absorption฀of฀1.9฀µg฀of฀cadmium฀per฀pack฀of.฀The฀elimination฀half-life฀of฀ cadmium฀is฀15.7฀years฀ [359] .฀In฀renal฀cancer฀patients฀from฀Finland,฀the฀mean฀concentra- tions฀of฀cadmium฀were฀9.43฀mgkg฀renal฀tissue฀for฀women฀and฀14.70฀mgkg฀renal฀tissue฀ for฀men.฀These฀levels฀are฀not฀regarded฀as฀very฀high฀ [360] ,฀but฀they฀are฀also฀associated฀with฀ reduced฀environmental฀exposure฀to฀heavy฀metals฀in฀Scandinavian฀countries฀over฀the฀last฀ 20฀or฀30฀years฀ [361,฀362] ,฀whereas฀higher฀levels฀have฀been฀measured฀in฀Japan฀ [363] . In฀ explant฀ cultures฀ of฀ human฀ bladder,฀ benzo[a]pyrene฀ undergoes฀ transformation฀ to฀ reactive฀metabolites฀which฀form฀adducts฀with฀DNA฀ [364] :฀these฀adducts฀are฀encountered฀ 2–20฀times฀more฀commonly฀in฀the฀bladder฀biopsy฀specimens฀of฀smokers฀than฀of฀non- smokers฀ [365,฀366] .฀The฀relevance฀of฀this฀inding฀to฀human฀bladder฀cancer฀is฀unknown.฀ Aryl฀ hydrocarbon฀ hydroxylase฀ AHH฀ activity฀ was฀ measured฀ in฀ kidney฀ cortex฀ biopsy฀ specimens:฀AHH฀activity฀was฀found฀to฀be฀slightly฀higher฀in฀cancer฀tissue฀compared฀with฀ healthy฀tissue฀ [367] . Nitrosamines:฀Tobacco฀contains฀procarcinogenic฀nitrosamines:฀in฀the฀urine฀of฀animals฀ as฀ well฀ as฀ in฀ that฀ of฀ infants฀ see฀ Chap.฀ 8,฀ nitrosamines฀ undergo฀ transformation฀ to฀ 4-methylnitrosamino-1-3-pyridyl-1-butanone฀NNK฀and฀its฀butanol฀analogue฀NNAL;฀ cf.฀Box฀3.1฀in฀Chap.฀3.฀NNK฀and฀NNAL฀are฀also฀formed฀in฀increased฀quantities฀by฀vari- ous฀bacterial฀strains฀responsible฀for฀bladder฀infections,฀leading฀to฀an฀increased฀carcinogen฀ burden฀ [368] .฀There฀is฀evidence฀to฀indicate฀that฀smoking฀produces฀alterations฀in฀chromo- some฀9฀and฀in฀p53฀and฀c-met฀which฀encourage฀bladder฀cancer฀ [369–372] .฀According฀to฀a฀ further฀study฀in฀89฀renal฀tumours,฀the฀frequency฀and฀pattern฀of฀p53฀mutations฀were฀similar฀ in฀transitional฀cell฀carcinomas฀of฀the฀bladder฀and฀the฀renal฀pelvis,฀and฀no฀inluence฀of฀ smoking฀or฀of฀phenacetin฀abuse฀could฀be฀identiied฀ [373] . 4-Aminobiphenyl฀adducts:฀At฀low฀nicotine-cotinine฀levels,฀N-acetyltransferase฀poly- morphism฀leads฀to฀high฀4-aminobiphenyl฀adduct฀levels฀in฀slow฀acetylators฀ [374] .฀These฀